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Neuromuscular Disorders 26 (2016) 754–759
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Developmental milestones in type I spinal muscular atrophy

Roberto De Sanctis a, Giorgia Coratti a, Amy Pasternak b, Jacqueline Montes c, Marika Pane a,
Elena S. Mazzone a, Sally Dunaway Young c, Rachel Salazar c, Janet Quigley b, Maria C. Pera a,
Laura Antonaci a, Leonardo Lapenta a, Allan M. Glanzman d, Danilo Tiziano e,
Francesco Muntoni f, Basil T. Darras b, Darryl C. De Vivo c, Richard Finkel g, Eugenio Mercuri a,*
a
Paediatric Neurology Unit, Catholic University and Centro Clinico Nemo, Rome, Italy
b
Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, USA
c
Department of Neurology, Columbia University Medical Center, New York, USA
d
Department of Physical Therapy, The Children’s Hospital of Philadelphia, Philadelphia, USA
e
Institute of Genetics, Catholic University, Rome, Italy
f
Dubowitz Neuromuscular Centre, UCL Institute of Child Health & Great Ormond Street Hospital, London, UK
g
Nemours Children’s Hospital, University of Central Florida College of Medicine, Orlando, USA
Received 14 July 2016; received in revised form 17 September 2016; accepted 2 October 2016

Abstract
The aim of this retrospective multicentric study was to assess developmental milestones longitudinally in type I SMA infants using the
Hammersmith Infant Neurological Examination. Thirty-three type I SMA infants, who classically do not achieve the ability to sit unsupported,
were included in the study. Our results confirmed that all patients had a score of 0 out of a scale of 4 on items assessing sitting, rolling, crawling,
standing or walking. A score of more than 0 was only achieved in three items: head control (n = 13), kicking (n = 15) and hand grasp (n = 18). In
these items, the maximal score achieved was 1 out of a scale of 4, indicating only partial achievement of the milestone. Infants with symptom onset
after 6 months of age had longer preservation of a score of 1 when compared to those with onset before 6 months of age. Our results suggest that
even when current standards of care are applied, developmental milestones are rarely even partially achieved as part of natural history in type I
SMA infants. No infants in this study achieved a major milestone such as rolling over, or sitting independently, which would therefore represent
robust outcomes in future interventional trials.
© 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/
by/4.0/).
Keywords: Spinal muscular atrophy; Hammersmith Infant Neurological Examination; Outcome measures; Motor milestones

1. Introduction due to improvements in the standards of care, with the

possibility to opt for respiratory and nutritional support [4,5].
Spinal muscular atrophy (SMA) is an autosomal recessive
The increased survival and the advent of different therapeutic
motor neuron disorder caused by mutations in the survival of
approaches have highlighted the need for a better definition of
motor neuron 1 (SMN1) telomeric gene, resulting in a reduced
the natural history of type I SMA especially as far as the
amount of functional full-length SMN protein. In children,
acquisition of functional milestones is concerned, and for
SMA is classified into 3 phenotypes based on age at onset and
identification of appropriate tools to follow the progression of
maximal motor function achieved [1,2].
the disease. A few attempts have been made recently to develop
Type I SMA is characterized by inability to sit unsupported
clinical tools specifically designed to assess motor function in
and by onset within 6 months of age [2,3]. Survival, typically
weak infants, such as the CHOP INTEND [6], or to adapt
limited to the first year, has increased in the last few decades,
existing scales, such as the TIMP [7,8]. These scales have
helped us to identify the variability of the phenotype and to
assess the rapid progression of the disease. Little attempt has
* Corresponding author. Pediatric Neurology, Catholic University, Largo
Gemelli 8, 00168 Rome, Italy. Fax: +390630154363. been made to monitor developmental milestones in these infants
E-mail address: eumercuri@gmail.com (E. Mercuri). as, by definition, they are unable to sit and only a minority of
http://dx.doi.org/10.1016/j.nmd.2016.10.002
0960-8966/© 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/
4.0/).
 R. De Sanctis et al. / Neuromuscular Disorders 26 (2016) 754–759
them will acquire the milestones of head control and/or rolling
over which are subsequently lost. Other important milestones,
such as crawling or standing, are not achieved in type I SMA
infants. However, no systematic study has assessed longitudinally
the acquisition of motor milestones in type I SMA infants
receiving current standards of care.
The aim of this study was to report the longitudinal use of a
module capturing developmental milestones in infancy, performed
as part of the Hammersmith Infant Neurological Examination
(HINE) [9,10], in type I SMA infants. More specifically, we
set out to investigate whether developmental milestones are
achieved at any stage during the first years of life in these
infants and, if achieved, to assess possible changes over time.
2. Materials and methods
This retrospective study was performed by collecting data from
different existing large multicentric datasets, including one
network based in the United States (the Pediatric Neuromuscular
Clinical Research Network for SMA) and one in Italy, in the period
between 2010 and October 2014.
All patients had a genetically confirmed diagnosis of SMA
with a homozygous deletion of exon 7 in the SMN1 gene, and a
clinically confirmed diagnosis of type I SMA.
The diagnosis of SMA was made by the principal investigator
at each site who also classified them according to the Dubowitz’s
Fig. 1. HINE scoring module illustrating the motor developmental milestones.
755
decimal classification [11] and to the recently proposed
classification in 3 subtypes [4,12]: type IA presentation at birth
with joint contractures and need for respiratory support, or onset
of motor and respiratory involvement in the first week; type IB,
symptom onset after neonatal period, usually before age 3
months, head control never achieved; and type IC, onset after
neonatal period, usually between 3 and 6 months, head control
achieved.
Previously identified patients, followed up in our clinics, and
newly diagnosed patients were enrolled. All eligible patients
were offered participation. We included all infants who had at
least two or more assessments over the following two years.
The study was approved by the individual institutional
review boards at the participating sites.
Study visits were scheduled at baseline, when first assessed,
and, when possible, every 2–3 months until the age of 12
months and every 6 months thereafter, depending on the infant’s
health and ability to travel.
The HINE [9] is a simple and scorable method for assessing
infants between 2 and 24 months of age, including different
aspects of neurological examinations as cranial nerves, posture,
movements, tone and reflexes. A separate section includes eight
selected motor items which document developmental progress
(Fig. 1). It provides a summary of motor developmental milestones
giving not only the opportunity to record the age at which the
various milestones were achieved but also allowing one to
756 R. De Sanctis et al. / Neuromuscular Disorders 26 (2016) 754–759

quantify intermediate steps leading to the full achievement of
the milestone. Each item provides the opportunity to score the
level of development on a 5 point scale with 0 as absence of
the activity. These milestones were designed according to the
gradient of normal maturation, with normative values adapted
from Illingworth’s work [13]. These items are more granular
than the World Health Organization’s motor milestones, which
capture sitting without support, hands-and-knees crawling,
standing with assistance, standing alone, walking with assistance
and walking alone [14].
The HINE module, on the other hand, is shorter and includes
less items of the motor component of the Bayley scales of
infants and toddler development that include many items that
are not relevant to type I SMA and is more fatiguing for such
fragile infants.
8 months. The age when they were first assessed was between 2
and 9 months.
Seven infants, who were at the severe end of the spectrum of
weakness and had early presentation with motor and respiratory
involvement within the first week, were classified as 1.1,
using the Dubowitz decimal system, or as type IA according
to the recent classification. Two other infants, who achieved
head control, were at the other end of the spectrum, and
were classified as 1.9, or type IC according to the recently
proposed classification. In both, onset of signs was around 7–8
months.
Twenty-four infants had the more typical course of type I
SMA, and were classified as 1.5, or type IB. In all 24 the onset
was after the first week but before the age of 5–6 months. Two
of these 24 achieved transient head control.

2.1. Statistical analysis

The distribution of scores was plotted for individual infants
for each item plotting longitudinal results according to age.
3. Results
Thirty-three infants fulfilled the inclusion criteria and were
included in the study. Their age at onset ranged between 1 and
3.1. Motor developmental milestones
3.1.1. Head control
All 7 infants at the weakest end of the spectrum had scores
of 0 on all the assessments.
Among the 24 infants in the main group, 11 had a score of 1
(wobbles) on at least one assessment, 13 had a score of 0 on all
assessments. None had a score of 2 or above (Fig. 2).

Fig. 2. Longitudinal data of the item assessing the ability to control the head in 24 typical type I SMA infants (from number 1 to 24) and in 2 stronger type I infants
with late onset (25–26, shaded). Each line represents the different assessments in the same patient linked by a dotted line. ● = score 0, ○ = score 1, V = ventilation;
G = gastrostomy; T = tracheostomy). The seven weakest patients with onset within the first week (type IA or 1.1 according to Dubowitz) were not added to the figure
as they all had a score of 0 in all assessments.
 R. De Sanctis et al. / Neuromuscular Disorders 26 (2016) 754–759 757

Fig. 3. Longitudinal data of the item assessing voluntary grasp in 24 typical type I SMA infants (from number 1 to 24) and in 2 type I infants with late onset (25–26,
shaded). Each line represents the different assessments in the same patient linked by a dotted line. ● = score 0, ○ = score 1, V = ventilation; G = gastrostomy;
T = tracheostomy). The seven patients with onset within the first week (type IA or 1.1 according to Dubowitz) were not added to the figure as they all had a score
of 0 in all assessments.

Infants who had a score of 0 never achieved higher scores on
subsequent assessments.
The 2 stronger infants with late onset had a score of 1 that
persisted throughout the assessments over the following 2
years.
3.1.2. Voluntary grasp
All 7 infants at the weakest end of the spectrum had a score
of 0 on all the assessments.
Among the 24 infants in the main group, 17 had a score of 1
(using whole hand) on at least one assessment, and 7 had a
score of 0 on all assessments. None had a score of 2 or above
(Fig. 3).
None of the infants who had a score of 0 on one assessment
had better scores on the subsequent assessments.
The 2 stronger infants with late onset achieved a score of 1
that persisted throughout the assessments over the following 2
years.
3.1.3. Ability to kick
All 7 infants at the weakest end of the spectrum had a score
of 0 on all the assessments.
Among the 24 infants in the main group, 13 had a score of 1
(gravity-eliminated movements) on at least one assessment, and
11 had a score of 0 on all assessments. None had scores of 2 or
above (Fig. 4). Only one of the infants who had a score of 0
achieved a score of 1 on subsequent assessments. The 2
stronger infants with late onset had a score of 1 that persisted
throughout the assessments over the following 2 years.
3.1.4. Other items
All infants in this study had a score of 0 on all visits in all
the remaining 5 items (sitting, rolling, crawling, standing,
walking).
3.1.5. Gastrostomy and ventilator support
In the main group, 15 of the 24 infants underwent
gastrostomy for swallowing problems and/or failure to thrive,
10 started non-invasive ventilation and 5 had tracheostomy.
None had any improvement following the introduction of any of
these procedures. In the few patients in whom the scores on
individual items were 1 at the time these procedures were
introduced, a score of 1 was not always maintained (Figs. 2–4).
4. Discussion
Improvements in standards of care with the more systematic
use of optimal respiratory care including non-invasive ventilation
and cough augmentation techniques and better management of
nutritional issues have resulted in improved survival in type I
SMA in the last decade. This has raised the question of whether
758 R. De Sanctis et al. / Neuromuscular Disorders 26 (2016) 754–759

Fig. 4. Longitudinal data of the item assessing ability to kick in 24 typical type I SMA infants (from number 1 to 24) and in 2 type I infants with late onset (25–26,
shaded). Each line represents the different assessments in the same patient linked by a dotted line. ● = score 0, ○ = score 1, V = ventilation; G = gastrostomy;
T = tracheostomy). The seven patients with onset within the first week (type IA or 1.1 according to Dubowitz) were not added to the figure as they all had a score
of 0 in all assessments.

the improved survival is also associated with possible acquisition
of motor developmental milestones over time.
In order to capture possible changes in the achievement of
motor developmental milestones in infancy, we used a module
extracted from the HINE, an assessment of global neurological
function and motor developmental milestones in infants that
can be used from the age of 2–3 months. The HINE has already
been used in several clinical groups [15] and has been validated
in typically developing children [9]. Using the developmental
module from the HINE we were able to confirm that motor
developmental milestones are only rarely acquired in type I
SMA infants after the diagnosis is made.
Not surprisingly, infants with the most severe phenotype
who also had very early onset of clinical signs never acquired
any motor developmental milestones, showing a score of 0 on
all of the 8 items at all times.
In contrast, scores higher than 0 could be observed in three
of the items in the cohort of infants with onset after the first
week of life.
By definition, type I SMA infants are unable to sit
unsupported. Our results confirmed that none of the infants
achieved independent sitting nor any other of the subsequent
milestones, such as crawling or standing in which all patients had
a score of 0 at all times. This was also true with the 2 stronger late
onset infants who were at the stronger end of the spectrum.
A score higher than 0 was only achieved in head control
(n = 13), kicking (n = 15) and hand grasp (n = 18). It is of interest
that even in those items, the maximal score achieved was 1 out of
a scale of 4, indicating only partial achievement of the milestone.
Partial head control was only achieved in 11 infants and was
reported as wobbling. This was transient in the infants in the
main cohort and sustained over several assessments in the 2
stronger infants with late onset. None achieved a constant full
head control for more than 15 seconds.
Thirteen infants were able to kick horizontally on at least one
assessment but legs did not lift with full antigravity movements
at any time, including the 2 stronger infants.
Similarly, although the item exploring hand grasp was not
specifically designed to capture changes in weak infants but is
mainly assessing development of fine motor skills, only a few
infants achieved the ability to use the whole hand and only the
2 stronger infants developed better hand grip.
Overall, when present, a score of 1 was found in younger
infants on their first assessments and, with only one exception,
none showed any improvement from 0 to 1 on subsequent
evaluations. Therefore, increased survival does not appear to
 R. De Sanctis et al. / Neuromuscular Disorders 26 (2016) 754–759
increase the possibility of acquiring developmental milestones
over time, or to improving their scores even if a full milestone
is not achieved. This finding, in fact, is not surprising as several
studies have reported progressive loss of motor neurons in
both animal models and humans; using neurophysiological
biomarkers, like CMAP and MUNE, severe and substantial
postnatal progression of motor denervation has been shown in
the first months postnatally in type I SMA [16].
When we looked at the possible relationship between
ventilatory or nutritional support and developmental milestones,
the numbers were too small to allow a meaningful statistical
analysis but it was obvious that the introduction of gastrostomy
or ventilator support was not consistently associated either
with higher scores or with a longer persistence of a score
of 1.
This may be explained by the fact that while better standards
of care may facilitate well-being and increased survival, the
need for ventilation or gastrostomy is, in most cases, a sign that
the disease has already progressed and is less likely to be
associated with subsequent improvements.
One of the limitations of the study is its retrospective nature;
however, data were collected over a limited period of time in
centers that were complying with current standards of care. In
order to avoid possible bias, the recruitment period was also
limited to the time when enrollment for clinical trials had not
started in the participating centers as, after that, we would have
included only the infants who, for some reason, were thought
not to be eligible for clinical trials. The relative small number of
patients was justified by the exclusion of infants who had only
one assessment and then decided to follow palliative care
locally. It is of interest, however, that infants who had only a
single assessment were generally performing very poorly and
none had a score of 2 (data not shown).
Our results suggest that even with current standards of care,
motor developmental milestones are rarely acquired, even partially,
as part of natural history in type I SMA infants. Even the
stronger ones, who had longer preservation of the scores of 1
when compared to the weaker infants with a more typical
course, failed to make any further gains after the first evaluation.
In future drug intervention studies, type I SMA infants who
achieve motor milestones beyond what is described here can
be attributed, with a strong probability, as being due to drug
effect and not to enhanced standard of care or prolonged survival.
Further longitudinal prospective studies, exploring, in more
detail, the correlation with standards of care, SMN2 copy numbers,
759
neurophysiology or biomarkers will help to further elucidate
the progression and the variability of the disease.
Funding
This study was funded by Famiglie SMA and Telethon
(Italy) (GSP 13002), the SMA Foundation (to PNCR) and SMA
Trust (UK).
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